title: Metastasis-associated protein 1 is an integral component of the circadian molecular machinery.
abstract: The mammalian circadian clock regulates the daily cycles of many important physiological processes, but its mechanism is not well understood. Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. Knockout of MTA1 in mice disrupts the free-running period of circadian rhythms under constant light and normal entrainment of behaviour to 12-h-light/12-h-dark cycles. The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. Moreover, MTA1 deacetylates BMAL1 at lysine 538 through regulating deacetylase SIRT1 expression, thus disturbing the CRY1-mediated negative feedback loop. These findings uncover a previously unappreciated role for MTA1 in maintenance of circadian rhythmicity through acting on the positive limb of the clock machinery.
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia 20037, USA [2].
authors.forename: Da-Qiang
authors.initials: DQ
authors.lastname: Li
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Pakala
authors.forename: Sirigiri Divijendra Natha
authors.initials: SD
authors.lastname: Reddy
authors.forename: Shaohua
authors.initials: S
authors.lastname: Peng
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Balasenthil
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Cheng Chi
authors.initials: CC
authors.lastname: Lee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rea
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001522:Behavior, Animal; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D017440:Photoperiod; D011401:Promoter Regions, Genetic; D055503:Protein Multimerization; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; C089320:MTA1 protein, human; C503336:Mta1 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D056926:CLOCK Proteins; C538944:Clock protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D006655:Histone Deacetylases